Adverse effects of RBC transfusions: A unifying hypothesis

描述(申请人提供)：输注红细胞(RBC)是美国医院最常见的治疗程序，通常对预防贫血患者的发病率和死亡率有效。然而，最近的研究表明，一些红细胞单位存在功能缺陷，损害了它们的疗效，实际上可能会对输血患者造成伤害。这些缺陷被称为“红细胞储存损伤”，在输血前储存的红细胞单位越长，这些缺陷似乎越多。输注有储存损伤的红细胞单位可能会对每年数千名患者造成不利影响，但目前我们没有准确的方法来识别这类单位。在这笔R01赠款的前一个资助期，我们观察到在血库储存过程中，供者与供者之间的红细胞代谢发生了意外的变化。基于这些数据，我们建议识别特定的代谢(人红细胞)和遗传(小鼠红细胞)生物标志物，这些生物标志物不仅可以反映由于储存时间和/或供体因素导致的红细胞功能的潜在差异，而且可以用于临床预测哪些红细胞单位可能导致输血后不良事件，以便在输血前将其从血液供应中移除。为了提供最有效的方法来实现这一目标，我们提出了一种综合研究努力，将(1)基于捐赠者/接受者的人类红细胞输注研究的相关性与(2)小鼠模型的机械力量相结合。人体研究将利用我们开发的方法来确定预测红细胞功能、输血后红细胞存活和血管效应的代谢生物标志物。小鼠研究的优势包括精细的遗传学特征，快速的繁殖时间，容易产生复杂的家系，以及表型-基因分析的能力。这些优势将被利用，方法是进行GWAS以确定小鼠红细胞储存表型的遗传标记，然后有选择地回交以建立所选遗传元件与感兴趣的表型之间的因果关系。拟议的协调调查允许每个模型利用其独特的优势，同时弥补固有的弱点，从而提供对选定的生物标志物的有效交叉验证。这些研究将延长在前一个资助期开始的工作，并将导致对红细胞生物标志物的验证，我们相信这些生物标志物将确定最有可能导致不良受者影响的红细胞单位，使它们能够在输血前被隔离。

DESCRIPTION (provided by applicant): Transfusion of red blood cells (RBCs), the most common therapeutic procedure performed in US hospitals, is usually effective at preventing morbidity and mortality in anemic patients. However, recent studies indicate that some RBC units have functional defects that impair their efficacy and may actually cause harm to transfused patients. These defects, which appear to increase the longer RBC units are stored prior to transfusion, have been called "RBC storage lesions". Transfusion of RBC units with storage lesions may adversely affect thousands of patients annually, but at present we have no accurate methods to identify such units. During the previous funding period for this R01 grant, we observed unexpected donor-to-donor variability in RBC metabolism during blood bank storage. Based on these data, we propose to identify specific metabolic (human RBCs) and genetic (murine RBCs) biomarkers that not only reflect the underlying differences in RBC function due to storage time and/or donor factors, but also can be used clinically to predict which RBC units may cause adverse post-transfusion events, allowing them to be removed from the blood supply before transfusion. To provide the most powerful approach to achieve this goal, we propose an integrated research effort that combines (1) the relevancy of donor/recipient-based human RBC transfusion investigations, with (2) the mechanistic power of mouse models. The human studies will utilize methodologies we have developed to identify metabolic biomarkers that predict RBC function, post-transfusion RBC survival, and vascular effects. The advantages of mouse studies include finely characterized genetics, rapid breeding times, ease of generating complex pedigrees, and the power of phenotype-genotype analysis. These advantages will be exploited by performing GWAS to identify genetic markers for mouse RBC storage phenotypes, and then selectively backcrossing to establish causality between selected genetic elements and phenotypes of interest. The proposed coordinated investigations allow each model to be used for its unique strengths, while compensating for intrinsic weaknesses, and thus provides efficient cross- validation of selected biomarkers. These studies will extend work started during the previous funding period, and will lead to the validation of RBC biomarkers that we believe will identify RBC units most likely to cause adverse recipient effects, allowing them to be sequestered prior to transfusion.